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Methyl and ethyl nicotinate-riboside-5-phosphates, preparation thereof and methods of use thereof

Pending Publication Date: 2021-12-16
CORNELL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a chemical compound of formula (I) and its salt, which can increase the production of NAD+ in cells and improve the density of mitochondria (the powerhouse of cells). The compound can be prepared using a specific process involving a series of chemical reactions. Its technical effects include improving cell metabolism, increasing cell energy production, and promoting cell survival.

Problems solved by technology

This strategy is inefficient in terms of time, cost, and particularly yields.

Method used

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  • Methyl and ethyl nicotinate-riboside-5-phosphates, preparation thereof and methods of use thereof
  • Methyl and ethyl nicotinate-riboside-5-phosphates, preparation thereof and methods of use thereof
  • Methyl and ethyl nicotinate-riboside-5-phosphates, preparation thereof and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0106]This example demonstrates a general synthesis of alkyl (β-nicotinic ribosides.

[0107]Methyl (β-nicotinic riboside and ethyl β-nicotinic riboside were synthesized as described in U.S. Pat. No. 8,106,184, the disclosure of which is incorporated herein by reference.

[0108]General procedure for the synthesis of nicotinate riboside mononucleotides. To a solution of nicotinate riboside in triethyl phosphate was added 2.5 eq. POCl3 at 0° C. The reaction mixture was stirred at 0° C. for 16 h and then neutralized with cold saturated NaHCO3 solution (pH=7). The reaction mixture was concentrated under reduced pressure to minimum volume, and ethyl acetate was added thereto. Filtration afforded pure nicotinate riboside mononucleotide as a solid.

example 2

[0109]This example demonstrates a synthesis of ((2R,3R,4S,5R)-3,4-dihydroxy-5-(3-(ethoxycarbonyl)pyridin-1-ium-1-yl)tetrahydrofuran-2-yl)methyl hydrogen phosphate.

[0110]1-((2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3-(ethoxycarbonyl)pyridin-1-ium trifluoromethanesulfonate (20 mg, 0.085 mm) and triethyl phosphate (1 ml) were placed in a flame-dried round-bottom flask. The mixture was cooled to 0° C., and POCl3 (65 mg, 0.4 mmol) was added dropwise to the mixture. The reaction mixture was stirred at the same temperature for 16 h. After completion, the reaction mixture was neutralized with cold saturated NaHCO3 solution (pH=7). The resulting solution was directly concentrated under reduced pressure to minimum volume, and 2 ml of ethyl acetate was added thereto. Filtration afforded pure compound as a white solid. 1H NMR (500 MHz, D2O): 67 .

example 3

[0111]This example demonstrates the effect of nicotinic acid mononucleotide on intracellular NAD+ levels in HEK293 and Neuro2a cells.

[0112]The ability of nicotinic acid mononucleotide, NaMN, to serve as an NAD+ enhancing agent in mammalian cell lines, Neuro2a and HEK293 cells was examined after an 8 h incubation. NaMN was added to cell growth media at a concentration of 1 mM. All cell treatments were done in duplicate. Nicotinamide riboside (NR) at 1 mM concentration was performed as a positive control. Untreated cells served as negative controls. Cells were treated for the allotted time then harvested by trysin detachment and pelleting. Cells were counted by haemocytometer and then lysed by treatment with 100 μL perchloric acid (7%). Lysates were then neutralized by treatment with NaOH and K2PO4 solutions. NAD+ concentrations were determined by a diaphorase-based assay. NAD+ standards were also run to establish a standard curve. The results are graphically depicted in FIG. 1.

[0113]...

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Abstract

The invention provides a compound of formula (I): (I) wherein R is methyl or ethyl. The invention also provides a process for the preparation of the compound. The invention further provides a method for increasing cell NAD+ production or improving mitochondrial densities in a cell, wherein the method comprises administering to the cell a compound or salt of the invention.

Description

CROSS-REFERENCE TO A RELATED APPLICATION[0001]This patent application claims the benefit of U.S. Provisional Patent Application No. 62 / 739,567, filed October 1, 2018, which is incorporated by reference in its entirety for all purposes.BACKGROUND OF THE INVENTION[0002]Nicotinamide adenine dinucleotide (NAD) is an important co-enzyme and substrate in several biological pathways and biochemical reactions including ADP-ribosylation and protein deacetylation and as an essential redox co-factor for many enzymes. NAD participation in metabolism makes it an important metabolite in several biological processes, such as aging, apoptosis, DNA repair, transcriptional regulation, and immune response.[0003]NAD can be synthesized from different precursors containing pyridine moieties in several salvage pathways (nicotinamide (Nam), nicotinic acid (NA), and nicotinamide riboside (NR)) and in the de novo pathway from tryptophan. Many non-mammalian organisms use nicotinic acid (a form of vitamin B3) ...

Claims

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Application Information

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IPC IPC(8): C07H19/048A23L33/13C07H1/02
CPCC07H19/048C07H1/02A23L33/13A61P25/00
Inventor SAUVE, ANTHONY A.
Owner CORNELL UNIVERSITY
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